Method of modifying angiotensin receptor activity for mediation of pain

ABSTRACT

The present invention relates to a method of modifying Angiotensin II subtype 1 (AT 1 ) receptor activity for the treatment of premenstrual syndrome (PMS) and the symptoms associated therewith, and further relates to a method for the treatment of acute or chronic pain mediated by the sympathetic nervous system. The treatment includes the administration of an effective amount of an AT 1  antagonist. AT 1  antagonists are drugs that are capable of blocking AT 1  receptors present within the body throughout the central nervous system including the hypothalamus. By blocking the AT 1  receptor activity, hypothalamic nerve activity, and therefore, sympathetic nerve activity are modulated. Thus, an effective method for treating sympathetically mediated pain is provided, as well as an effective method for treating PMS. The AT 1  antagonist can be used alone or in combination with other drug therapies, for instance, non-steroidal anti-inflammatory drugs, antidepressants, opiod drugs, angiotensin converting enzyme inhibitors, and diuretics.

The present application is a 371 of PCT/US95/05312, filed Apr. 28, 1995,which is a continuation-in-part of U.S. Ser. No.08/235,468 filed Apr.29,1994, now U.S. Pat. No. 5,464,854.

FIELD OF THE INVENTION

The present invention relates to a method of modifying Angiotensin IIsubtype 1 (AT₁) receptor activity for the treatment of premenstrualsyndrome (PMS) and for the mediation and alleviation of pain. Morespecifically, the present invention relates to the use of AT₁antagonists to modulate sympathetic nerve activity as treatment for painand as treatment for PMS.

BACKGROUND OF THE INVENTION

The nervous system of the human body carries information in the form ofnerve impulses to and from all parts of the body in order to regulatebody activity. The nervous system consists of the central nervous system(CNS), including the brain and the spinal cord, which is responsible forintegrating all activities of the nervous system; and the peripheralnervous system, including the cranial nerves and the spinal nerves,which link the receptors and the effector organs with the brain andspinal cord. The autonomic nervous system controls many bodily functionsthat are not consciously directed. The autonomic nervous system issubdivided into the sympathetic and the parasympathetic nervous systems,which individually control and coordinate various functions of bodyorgans.

It is well known that the hypothalamus is an area of the brain whichintegrates hormonal and autonomic activity within the body, andcoordinates physiological, behavioral and mood responses. Thehypothalamus is the major central controller of the autonomic nervoussystem. Nearly every region of the brain sends signals to thehypothalamus. Pathways of nerve fibers descend from the brain andconnect through synapses with areas on the brain stem, and then descendto the spinal cord where they synapse with neurons in the lateralcolumns of white matter which represent collections of nerve cells.There is an intimate interconnection between the nerve pathways involvedin pain transmission and the sympathetic nervous system. (BasicNeurochemistry, Raven Press, 1994).

It is known that sympathetic functions and hypothalamic functions arepartly regulated by AT₁ receptors. It is also known that changing levelsof ovarian hormones can modify the density and function of AT₁receptors, as well as induce changes in the morphology of nerve cellswithin the central nervous system.

At present, there are known to be two distinct Angiotensin II receptorsubtypes: AT₁ and AT₂. Various drugs have been developed to block thereceptor activity of the AT₁ and AT₂ receptors. Such drugs are commonlyknown as AT₁ antagonists or AT₂ antagonists, referring to the type ofreceptor which is being blocked.

U.S. Pat. No. 5,246,943 to Blankley et al. discloses novel AT₂antagonists which may have utility in treating numerous disordersincluding those associated with pain, and may have further utility inthe regulation of the menstrual cycle. AT₁ and AT₂ receptors aredistinct subtypes which have different functions. Blankley recognizesthis and discloses a group of AT₂ antagonists which have no AT₁antagonist properties.

U.S. Pat. No. 4,912,096 to Sudilovsky and U.S. Pat. No. 4,931,430 toSudilovsky et al. disclose the use of ACE inhibitors as treatment forlong term chronic and acute anxiety and depressive disorders. Suchdisorders are distinctly different from PMS in that they are typicallylong-term disorders which worsen in time and require long-term systemicmedication. Symptoms associated with PMS, on the other hand areintermittent, occurring during the luteal phase of the menstrual cycleand with subsequent remission. Sudilovsky specifically addresses theenkephalinase inhibitory properties of ACE inhibitors and their effectson opiod receptor activity in treating depression and anxiety. Further,the Sudilovsky references do not suggest the use of AT₁ antagonists.

PMS can have a debilitating effect on humans, through a variety ofsymptoms including changes in libido, erratic behavior, lack ofemotional control, tension, mood swings, restlessness, insomnia,feelings of guilt, low self image, lack of attention span, anger, labilemood, irritability, hot flashes, cold flashes, palpitations, chills,sweating, dizziness, edema, breast tenderness, bloating, nausea,headaches, pelvic pain, abdominal pain, musculoskeletal pain andfatigue.

Further, pain can manifest itself in the human body due to a variety ofreasons including acute or chronic pain associated with trauma, injury,surgery, burns, lower back disorders and arthritis, as well as variousconditions including fibromyalgia, myofascial pain syndrome, chronicpain syndromes, the syndrome of menstrual migraine and pain syndromeunrelated to injury which might include symptoms such as headache,musculoskeletal pain, pain localized to one side of the body, lower backpain, complex regional pain syndrome and sympathetically maintained painsyndrome. It should also be noted that various pain syndromes canproduce physical manifestations of sympathetic dysfunction, for example,Raynaud phenomenon (severe vasoconstriction of the blood vessels in thefingers), edema, numbness, paresthesia (abnormal spontaneoussensations), allodynia (pain caused by non-painful stimuli) andsweating. Therefore the sympathetic nervous system is involved in thetransmission of painful impulses and plays a role in the manifestationof the aforementioned painful conditions.

Treatment for PMS has typically involved symptomatic treatment andrelief, using conventional medications such as aspirin, antipyretics,diuretics, ibuprofen, and the like. However, these conventionaltreatments merely addressed the symptoms associated with PMS, and failedto address the underlying cause of the symptoms.

Further, effective treatment for pain has typically involvedconventional medications such as morphine, which merely reduce theperception of pain by blocking the opiod pathway. Such opiod drugs canbe disabling for patients, and have a variety of undesirable sideeffects.

As such, a need exists for a method for the treatment of premenstrualsyndrome and the symptoms associated therewith, as well as for a methodfor the treatment or modulation of acute or chronic pain mediated by thesympathetic nervous system.

SUMMARY OF THE INVENTION

The present invention concerns a method of treating premenstrualsyndrome and painful conditions by modulating the activity of AT₁receptors and affecting changes in the functioning of central andperipheral components of the autonomic nervous system.

In one embodiment of the present invention, a method of treating acuteor chronic pain mediated by the sympathetic nervous system is provided,which method includes administering an effective amount of an AT₁antagonist. Such administration reduces the activity of the AT₁receptors, thus modulating the sympathetic nerve activity and/or thehypothalamic activity.

A further embodiment of the present invention provides a method oftreating sympathetically mediated pain disorders which includesadministering an effective amount of an AT₁ antagonist.

In yet a further embodiment of the present invention, a method oftreating premenstrual syndrome is provided, which includes administeringto a female during the luteal phase or symptomatic period of a menstrualcycle an effective amount of an AT₁ antagonist.

A non-limiting list of AT₁ antagonists useful in the present inventioninclude: sodium2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo(4,5-b)pyridin-3-yl)methyl)quinolin-2-yl)benzoate;4'-((1,4'-dimethyl-2'-propyl(2,6'-bi-1H-benzimidazol)-1'-yl)methyl)-(1,1'-biphenyl)-2-carboxylicacid;5-methyl-7-propyl-8-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1,2,4-triazolo(1,5-c)pyrimidin-2(3H)-one;1-(N-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl)-N-valerolylaminomethyl)cyclopentane-1-carboxylicacid;1-((2'((i-pentyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-(2-(N-butyryl-N-pyridin-3-ylamino)propionyl)-4-ethyl-2-propyl-1H-imidazole,potassium salt;4-ethyl-2-n-propyl-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic acid; 1H-Imidazole-5-carboxylic acid,4-(pentafluoroethyl)-2-propyl-1-((2'-1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl-(CAS); 1H-imidazole-5-methanol,2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-,monopotassium salt (CAS);3-((2'carboxybiphenyl-4-yl)methyl)-2-cyclopropyl-7-methyl-3H-imidazo(4,5-b)pyridine;1H-imidazole-5-carboxylic acid,1-((3-bromo-2-(1H-tetrazol-5-yl)phenyl)-5-benzofuranyl)methyl)-2-butyl-4-chloro-(CAS);2-butyl-4-chloro-1((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxylicacid,-1-(ethoxycarbonyloxy)ethylester, K+ salt;3-methoxy-2,6-dimethyl-4-((2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methoxy)pyridine;6-(benzoylamino)-7-methyl-2-propyl-3-((2'-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)(1,1')-biphenyl-4-yl)methyl)-3H-imidazo(4,5-b)pyridine;6-(N-acetyl-N-methylamino)-2-propyl-3-(2'-tetrazol-5-yl)-biphen-4-yl)methyl)quinazolin-4-(3H)-one;1,1-dimethylethyl-2-(4'-(1-(3-(5-butyl)-2-oxo-(2-trifylphenyl)-(1,3,4)-trazolyl)methyl)biphenyl)sulfonylaminocarboxylate;5-((3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl)-2-(2-(1H-tetrazol-5-ylphenyl))pyridine;2-n-butyl-4-spirocyclopentane-1-(((2'-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-imidazolin-5-one;3-(2-butyl-1-(4-carboxybenzyl)-1H-imidazol-5-yl)-2-(2-thienylmethyl)-2-(E)-propenoicacid;6-butyl-2-(2-phenylethyl)-5-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-4(1H)-Pyrimidinone;2,7-diethyl-5-((2'-(5-tetrazolyl)biphenyl-4-yl)methyl)-5H-pyrazolo(1,5-b)(1,2,4)triazole;1H-imidazole-5-carboxylic acid,1-((3-bromo-2-(2-(1H-tetrazol-5yl)phenyl)-5-benzofuranyl)methyl)-2-butyl-4-chloro-(CAS);1H-benzimidazole-7-carboxylic acid,2-ethoxy-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-,1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester,-(CAS); methyl2-((4-butyl-2-methyl-6-oxo-5-((2'-(1H-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl)methyl)-1(6H)-pyrimidinyl)methyl)-3-thiophencarboxylate;and (S)-N-valeryl-N-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-valine,and mixtures thereof.

The present invention contemplates the administration of the AT₁antagonist by any efficacious method including orally, intravenously,intra-nasally and epidurally. The AT₁ antagonist is preferablyadministered in an amount from about 0.5 to about 800 mg over a periodof about twenty-four hours.

In an alternate embodiment of the present invention, the AT₁ antagonistis administered in combination with a drug selected from the groupconsisting of a non-steroidal anti-inflammatory drug, an opiod drug, anantidepressant drug, an angiotensin converting enzyme inhibitor, adiuretic, and mixtures thereof.

A non-limiting list of non-steroidal anti-inflammatory drugscontemplated for such a use includes ibuprofen, diclofenac, piroxcam,naproxen sodium, naproxen, nambumetone, etodolac, ketorolactromethamine, acetylsalicylic acid, sodium salicylate, diflunisal,sulindac, tolmetin sodium, mefanamic acid, meclofenamate sodium,fenoprofen and mixtures thereof.

A non-limiting list of opiod drugs contemplated for such a use includescodeine, morphine sulfate, hydroxymorphone, hydrocodone, oxycodone,meperidine and mixtures thereof.

A non-limiting list of antidepressant drugs contemplated for such a useincludes amytriptyline HCl, amoxapine, desipramine HCl, doxepine HCl,imipramine HCl, maprotiline HCl, phenelzine sulfate, fluoxetine HCl,sertraline HCl, trazodone and mixtures thereof.

A non-limiting list of angiotensin converting enzyme inhibitorscontemplated for such a use includes quinipril, enalapril, captopril,benazepril, ramipril, trandolapril, lisinopril, fosinopril and mixturesthereof.

A non-limiting list of diuretics contemplated for such a use includesbenzthiazide, bumetanide, chlorthiazide, chlorthalidone, ethacrynicacid, furosemide, hydrochlorothiazide, hydroflumethiazide, metolazone,polythiazide, spironalactone, triameterene and mixtures thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the hormonal changes occurring during the humanmenstrual cycle.

FIG. 2 depicts the patterns of PMS symptoms experienced by patients.

FIG. 3a and FIG. 3b depict the results of a study on circulating ovarianhormone levels showing patients treated with daily injections of GnRHagonist as compared with patients treated with placebo.

FIG. 4 depicts the effects of the same treatment as FIGS. 3a and 3b,showing the severity of PMS symptoms.

FIG. 5 shows the effects of cyclic ovarian hormone changes on AT₁receptors.

FIG. 6 shows a comparison between the normal number of AT₁ receptors inmale and female rats as compared with rats which have beenovariectomized and subsequently treated with estrogen and progesterone.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with the treatment of sympatheticallymediated pain as well as with the treatment of premenstrual syndrome(PMS) by the administration of AT₁ antagonists.

As stated previously, the hypothalamus is known to integrate hormonalactivity and autonomic nervous system activity. Table I demonstrates theprincipal hypothalamic regulatory mechanism. (Ganong, W. F., Review ofMedical Physiology, 14th ed., Appleton and Lange, 1989).

                                      TABLE I                                     __________________________________________________________________________    PRINCIPAL HYPOTHALAMIC REGULATORY MECHANISM                                   FUNCTION    AFFERENTS FROM                                                                             INTEGRATING AREAS                                    __________________________________________________________________________    Temperature Cutaneous Cold                                                                             Anterior Hypothalamus                                Regulation  Receptors: Temperature-                                                                    (Response to Heat)                                               Sensitive Cells in                                                                         Posterior Hypothalamus                                           Hypothalamus (Response to Cold)                                   Neuroendocrine                                                                            Emotional Stimuli,                                                                         Dorsomedial and Posterior                            Control of  Probably via Limbic                                                                        Hypothalamus                                         Catecholamines                                                                            System                                                            Vasopressin Osmoreceptors, Volume                                                                      Supraoptic and                                                   Receptors, Others                                                                          Paraventricular Nuclei                               Oxytocin    Touch Receptors in                                                                         Supraoptic and                                                   Breast, Uterus,                                                                            Paraventricular Nuclei                                           Genitalia                                                         Thyroid-Stimulating                                                                       Temperature Receptors,                                                                     Dorsomedial Nuclei and                               Hormone (Thyrotropin,                                                                     Perhaps Others                                                                             Neighboring Areas                                    TSH) via Thyrotropin-                                                         Stimulating Hormone                                                           (TRH)                                                                         Adrenocorticotropic                                                                       Limbic System (Emotional                                                                   Paraventricular Nuclei                               Hormones (ACTH) and                                                                       Stimuli);Reticular                                                B-Lipotrophin (B LPH)                                                                     Formation ("Systemic"                                             via Corticortropin-                                                                       Stimuli); Hypothalamic                                            Releasing Hormone                                                                         or Anterior Pituitary                                             (CRH)       Cells Sensitive to                                                            Circulating Blood                                                             Cortisol Level;                                                               Suprachiasmatic Nuclei                                                        (Diurnal Rhythm)                                                  Follicle-Stimulating                                                                      Hypothalamic Cells                                                                         Preoptic Area, Other                                 Hormone (FSH) and                                                                         Sensitive to Estrogens;                                                                    Areas                                                Luteinizing Hormone                                                                       Eyes, Touch Receptors in                                          (LH) via Luteinizing-                                                                     Skin and Genitalia of                                             Hormone-Releasing                                                                         Reflex Ovulating Species                                          Hormone (LHRH)                                                                Prolactin via                                                                             Touch Receptors in                                                                         Arcuate Nucleus, Other                               Prolactin-Inhibiting                                                                      Breasts, Other Unknown                                                                     Areas (Hypothalamus                                  Hormones (PIH) and                                                                        Receptors    Inhibits Secretion)                                  Prolactin-Releasing                                                           Hormone (PRH)                                                                 Growth Hormone via                                                                        Unknown Receptors                                                                          Periventricular Nucleus,                             Somatostatin and         Arcuate Nucleus                                      Growth-Hormone-                                                               Releasing Hormone                                                             (GRH)                                                                         "Appetitive"                                                                              Osmoreceptors,                                                                             Lateral Superior                                     Behavior, Thirst                                                                          Subfornical Organ                                                                          Hypothalamus                                         Hunger      "Glucostat" Cells                                                                          Ventromedial Satiety                                             Sensitive to Rate of                                                                       Center, Lateral Hunger                                           Glucose Utilization                                                                        Center; Also Limbic                                                           Components                                           Sexual Behavior                                                                           Cells Sensitive to                                                                         Anterior Ventral                                                 Circulating Estrogen and                                                                   Hypothalamus Plus (in the                                        Androgen, Others                                                                           male) Piriform Cortex                                Defensive Reactions,                                                                      Sense Organs and                                                                           In Limbic System and                                 Fear, Rage  Neocortex, Paths Unknown                                                                   Hypothalamus                                         Control of Various                                                                        Retina via   Suprachiasmatic Nuclei                               Endocrine and                                                                             Retinohypothalalmic                                               Activity Rhythms                                                                          Fibers                                                            __________________________________________________________________________

It is also known that sympathetic functions and hypothalamic functionsare regulated by AT₁ receptors. Further, changing levels of hormonessuch as ovarian hormones can change the density and function of the AT₁receptors, as well as induce changes in the morphology of nerve cellsthroughout the central nervous system. In addition, the hypothalamus isthe known regulator of autonomic activity. AT₁ receptor function isinvolved in autonomic nervous regulation due to the presence in theanatomically known regulating areas of the hypothalamus. The presentinvention hypothesizes that since hormones can modify the density of AT₁receptors, they therefore modify the functioning of the sympatheticnervous system.

The menstrual cycle of the human female is divided into follicular andluteal phases. FIG. 1 shows the hormonal changes that occur during themenstrual cycle, such as estrogen 11 and progesterone 12. Days onethrough five are the days of the menses and correspond to the time whenthe menstrual flow is occurring. This period is sometimes referred to asthe menstrual phase, as seen in FIG. 1 as menstrual phase 10.Premenstrual syndrome is the cyclic recurrence in the luteal phase of acombination of physical, psychological and/or behavioral symptoms whichsignificantly impair social or occupational functioning. Most womenexperience symptoms for 1 to 14 days, usually beginning after ovulationwhich occurs approximately on day 14. Ninety percent (90%) ofmenstruating females exhibit some symptoms of PMS, but only 20-40% ofpatients are incapacitated to some degree or require therapy. Typically,PMS symptoms can be grouped, for example, as follows:

Affective/Cognitive Symptoms--i.e., changes in libido, unreasonableerratic behavior, lack of emotional control, tension, mood swings,restlessness, insomnia, feelings of guilt, low self image, distractable,inward anger, labile mood, irritability, cyclical depression andcyclical anxiety

Autonomic Symptoms--i.e., hot or cold flashes, palpitations, chills,sweating and dizziness

Somatic/Physical Symptoms--i.e., edema, breast tenderness, bloating ofthe abdomen or extremities, nausea, headache, pelvic or abdominal pain,and fatigue, muscular and joint pain

FIG. 2 shows several symptom patterns reported by patients who sufferfrom PMS. These symptom patterns correspond with a time when there arehigh levels of both estrogen 11 and progesterone 12 as seen in FIG. 1.The symptoms usually remit with the onset of menses or within a few daysafterwards. Also, as seen in FIG. 1, this remittance period is whenlevels of estrogen 11 and progesterone 12 are lowest.

Three studies have clearly shown the role of ovarian hormones in PMS.Muse, et al. demonstrated that medical ovariectomy by daily injectionsof a GnRH agonist reduced the cyclic hormonal changes of estrogen andprogesterone. (Muse, K. N.; Cetel, N. S.; Futterman, L. A.; Yen, S. S.C., The Premenstrual Syndrome: Effects of "Medical Ovariectomy", N EnglJ Med 311:1,345, 1984). Patients with moderate to severe PMS weretreated with placebo or GnRH agonist for three months and measurementsof hormone levels were made in the same patients during each course oftherapy. The results of this study are shown in FIGS. 3a and 3b. FIG. 3adepicts the level of estrogen in placebo-treated patients 13a ascompared to the level of estrogen in GnRH agonist-treated patients 13b.FIG. 3b depicts the level of progesterone in placebo-treated patients14a as compared to the level of progesterone in GnRH agonist-treatedpatients 14b. In the patients receiving the GnRH agonist, thefluctuations in ovarian hormones were abolished when compared to theplacebo-treated patients. This study also demonstrated the effects ofreducing ovarian hormones on PMS symptoms, shown in FIG. 4. Typicalphysical and behavioral symptoms which were shown to occur during theluteal phase with placebo treatment 15 were significantly reduced withGnRH agonist treatment 16.

In a second study, Casper et al. demonstrated how a series of patientswho underwent surgical ovariectomy showed complete resolution of PMSsymptoms. (Casper, R. F.; Hearn, M. T., The Effect of Hysterectomy andBilateral Oophorectomy in Women with Severe Premenstrual Syndrome, Am.J. Obstet. Gynecol. 162:105-9, 1990).

Finally, in a third study Hammarback et al. reported cyclical moodchanges in postmenopausal patients receiving sequential estrogen andprogesterone replacement therapy. (Hammarback, S.; Backstrom, T.; Holst,J.; von Schoultz, B.; Lyrenas, S., Cyclical Mood Changes as in thePremenstrual tension Syndrome During Sequential Estrogen-ProgesteronePostmenopausal Replacement Therapy, Acta Obstet Gynecol Scand 64:393,1985). Together these data clearly demonstrate the pivotal role ofovarian hormones in the genesis of PMS.

As noted above, PMS is characterized by multiple symptoms affectingvarious systems. If PMS is viewed as a single system dysfunction with asingle pathophysiology and multiple manifestations, one is led toconsider the hypothalamus as a connection between the cyclical changesand the symptoms. The hypothalamus regulates vegetative and endocrinefunction, and controls complex emotional and behavioral reactions byresponding to various stimuli and integrating these stimuli intoappropriate responses. A comparison of the hypothalamic functions andthe symptoms of PMS suggests a correlation between the two, in thatsymptoms which are commonly seen in PMS are related to the types ofresponses and behaviors typically associated with the hypothalamus. Areview of hypothalamic nuclei reveals that Angiotensin II and AT₁receptors are present within the hypothalamus and that these receptorsplay a key role in regulating the multiple functions and coordinatingactions of the hypothalamus.

Recent research has now shown that the hypothalamic AT₁ receptor densityand functions are regulated by the cyclic changes in estrogen andprogesterone. The AT₁ receptor is known to mediate the potentconstrictor effects on smooth muscle, (i.e. vascular), to mediate therelease of aldosterone from the adrenal cortex, and centrally activatesor facilitates the activity of the sympathetic nervous system. How theAT₁ receptor mediates angiotensin functions is uncertain, but thedistribution is different in various organs and tissues. It seemsprobable that ovarian hormones regulate Ang II receptor activity byaltering their density or binding characteristics. To demonstrate this,Grove et al. administered estrogen and progesterone to rats afterovariectomy. (Grove, K. L.; Speth, R. C.; Sylvester, P. W.; Brisk, K.P., Gonadal Steroids Alter Brain AnQiotensin II Receptors inOvariectomized Rats, Soc. For Neuroscience Abstracts, v 18, p. 1162,1992). The rats treated with such ovarian hormones showed an increase inthe number of Ang II receptors in the hypothalamic nuclei as comparedwith untreated rats. Further, as seen in FIG. 5, Seltzer et al. showedthat the level of Ang II binding 19 and the number of AT₁ receptors inthe dorsomedial arcuate nucleus of the hypothalamus of a rat is low atproestrus 17, which represents a low estrogen period, and increasessignificantly at estrus 18, which represents a high estrogen andprogesterone period during the luteal phase. (Seltzer, A. et al.,Reproductive Hormones Modulate Angiotensin II Receptors in theDorsomedial Arcuate Nucleus of the Female Rat, Endocrinol v133,pp939-941, 1993). This was confirmed, as seen in FIG. 6, whenovariectomized animals treated with exogenous estrogen and progesteroneshowed a similar increase in AT₁ receptors (as depicted at level 20),while non-treated animals showed no such increase (as depicted at level21).

The aforementioned references show a link between PMS and the cyclicalovarian hormone changes occurring in the female menstrual cycle.Further, the hypothalamus is known to regulate various physical andbehavioral functions associated with PMS. Still further, theaforementioned references show that the density of AT₁ receptors in thehypothalamus varies with the phase of the ovarian cycle, and thatestrogen and progesterone modulate AT₁ receptor density and function.When viewed in light of each other, the present invention contemplatesthat AT₁ receptors are important mediators in producing the symptoms ofPMS. It is therefore discovered that by intervening to modulate thefunction of the AT₁ receptors, an effective method of treatment for PMSis provided. The present invention accomplishes this effective treatmentby administering an effective amount of an AT₁ antagonist to a femaleduring the luteal phase or symptomatic period of a menstrual cycle.

It is further contemplated by the present invention that changes in thedensity of AT₁ receptors and the morphology of nerve cells haveconsequence in the perception and generation of pain. As described, painin humans manifests itself in numerous ways, some of which are directlyrelated to the functions of the sympathetic nervous system. Thesympathetic nervous system undergoes adaptive reactions in the presenceof pain, and, as mentioned above, an intimate interconnection existsbetween pain conducting nerve pathways and the sympathetic nervoussystem. As such, painful stimuli can produce many well-recognized painresponses that are controlled through the sympathetic nervous system,for example, sweating, tachycardia (rapid heart rate), and pupillarydilation. (Stanton-Hicks, M. "Pain and the Sympathetic Nervous System",American Academy of Pain Medicine, Pain Medicine Board Review Course,Feb. 17-19, 1995).

It is believed that the central nervous system adapts in the presence ofpain under various pathological conditions, and that neurohumoral andmorphological changes occur within the central nervous system as aresult of this adaptation. It is further believed that an increasedsensitivity to pain occurs as a result of the coalition of abnormalsensations, autonomic functions, somatomotor functions and endocrineresponses. As a result, sympathetic outflow to an affected part of thebody may actually generate pain, and spontaneous pain may in part bedependent on such sympathetic activity. The involvement of thesympathetic nervous system in pain is further suggested by the use oflocal injection of anaesthetic or surgical ablation of sympatheticnerves to relieve pain. For example, chemically or thermoelectricallyperformed sypathectomy is used to treat chronic lumbar disc pain orvisceral pain due to cancer. (Bradley, K. C., The Sypathetic NervousSystem and Pain, Advances in Pain Research and Therapy, v13, RavenPress, NY 1990).

Additionally, many painful disorders reflect variability in intensity inrelation to the menstrual cycle, for example, rheumatoid arthritis,epilepsy and menstrual migraine. Menstrual migraine, in particular,shows a variability of the hypothalamic responses in the luteal phase ofthe female menstrual cycle. One of the changes in response includes achange in autonomic regulation. Painful disorders such as fibromyalgia,myofascial pain syndrome and chronic fatigue syndrome are eight to 20times more common in females, typically those females between the agesof 25 to 45, which corresponds to the age group most commonly affectedby PMS. In fibromyalgia, there is a documented abnormality in thedexamethasone suppression test which reflects a change in thehypothalamic-pituitary axis. (Bennett, R. M., Textbook of Rheumatology,4th ed., W. B. Sanders Co., 1993).

Further, acute or chronic pain mediated by the sympathetic nervoussystem is known to occur in the body. Such pain can typically resultfrom trauma, injury, surgery, lower back disorders, arthritis, and thelike. In addition, various pain syndromes have a connection with thesympathetic nervous system, for example, fibromyalgia, myofascial painsyndrome, chronic pain syndromes, syndromes of menstrual migraine, painresulting from injury, and pain syndrome unrelated to injury which mightinclude symptoms such as headache, musculoskeletal pain, pain localizedto one side of the body, lower back pain, complex regional pain syndromeand sympathetically maintained pain syndrome. Such pain syndromes canproduce various physical manifestations within the body, for example,Raynaud phenomenon (severe vasoconstriction of the blood vessels in thefingers), edema, numbness, paresthesia (abnormal spontaneoussensations), allodynia (pain caused by non-painful stimuli) andsweating.

In all of the aforementioned pain syndromes as well as with PMS, thehypothalamus is responsible for some aspect of the generation of thesyndrome. Further, it is clear that in all of the aforementioned painsyndromes as well as with PMS, sympathetic and hypothalamic function aredisturbed. As mentioned, AT₁ receptors are present in the hypothalamus.Sympathetic function and hypothalamic function are known to be regulatedby these AT₁ receptors, as is parasympathetic nerve function. Thus, thepresent invention contemplates that any changes in the density of AT₁receptors and/or the morphology of nerve cells in the brain area willhave an effect on the perception of pain as well as PMS, andconsequentially effect any pain responses. In other words, it is thehypothalamus that determines the distress that an injured or sick personin pain experiences to a greater degree than just the sensory intensityof the pain.

AT₁ antagonists are drugs which are known for blocking AT₁ receptors.The present invention provides an effective method for the treatment ofacute or chronic pain mediated by the sympathetic nervous system byadministering an effective amount of an AT₁ antagonist. Further, thepresent invention provides an effective method for the treatment of PMSby administering to a female during the luteal phase or symptomaticperiod of the menstrual cycle an effective amount of an AT₁ antagonist.An effective amount is defined as that amount capable of reducing theAT₁ receptor activity sufficiently to provide relief for PMS or foracute or chronic pain mediated by the sympathetic nervous system.

AT₁ antagonists which are useful with the present invention for thetreatment of PMS and for the treatment of pain include, withoutlimitation, those selected from the group including: sodium2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo(4,5-b)pyridin-3-yl)methyl)quinolin-2-yl)benzoate;4'-((1,4'-dimethyl-2'-propyl(2,6'-bi-1H-benzimidazol)-1'-yl)methyl)-(1,1'-biphenyl)-2-carboxylicacid; 5-methyl-7-propyl-8-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1,2,4-triazolo(1,5-c)pyrimidin-2(3H)-one;1-(N-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl)-N-valerolylaminomethyl)cyclopentane-1-carboxylicacid;1-((2'((i-pentyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-(2-(N-butyryl-N-pyridin-3-ylamino)propionyl)-4-ethyl-2-propyl-1H-imidazole,potassium salt;4-ethyl-2-n-propyl-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic acid; 1H-Imidazole-5-carboxylic acid,4-(pentafluoroethyl)-2-propyl-1-((2'-1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl-(CAS);1H-imidazole-5-methanol,2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-,monopotassium salt (CAS);3-((2'carboxybiphenyl)-4-yl)methyl)-2-cyclopropyl-7-methyl-3H-imidazo(4,5-b)pyridine;1H-imidazole-5-carboxylic acid,1-((3-bromo-2-(1H-tetrazol-5-yl)phenyl)-5-benzofuranyl)methyl)-2-butyl-4-chloro-(CAS);2-butyl-4-chloro-1((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxylicacid,-1-(ethoxycarbonyloxy)ethylester, K+ salt;3-methoxy-2,6-dimethyl-4-((2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methoxy)pyridine;6-(benzoylamino)-7-methyl-2-propyl-3-((2'-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)(1,1')-biphenyl-4-yl)methyl)-3H-imidazo(4,5-b)pyridine;6-(N-acetyl-N-methylamino)-2-propyl-3-(2'-tetrazol-5-yl)-biphen-4-yl)methyl)quinazolin-4-(3H)-one;1,1-dimethylethyl-2-(4'-(1-(3-(5-butyl)-2-oxo-(2-trifylphenyl)-(1,3,4)-trazolyl)methyl)biphenyl)sulfonylaminocarboxylate;5-((3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl)-2-(2-(1H-tetrazol-5-ylphenyl))pyridine;2-n-butyl-4-spirocyclopentane-l-(((2'-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-imidazolin-5-one;3-(2-butyl-1-(4-carboxybenzyl)-1H-imidazol-5-yl)-2-(2-thienylmethyl)-2-(E)-propenoicacid;6-butyl-2-(2-phenylethyl)-5-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-4(1H)-Pyrimidinone;2,7-diethyl-5-((2'-(5-tetrazolyl)biphenyl-4-yl)methyl)-5H-pyrazolo(1,5-b)(1,2,4)triazole;1H-imidazole-5-carboxylic acid,1-((3-bromo-2-(2-(1H-tetrazol-5yl)phenyl)-5-benzofuranyl)methyl)-2-butyl-4-chloro-(CAS);1H-benzimidazole-7-carboxylic acid,2-ethoxy-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-,1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester,-(CAS); methyl2-((4-butyl-2-methyl-6-oxo-5-((2'-(1H-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl)methyl)-1(6H)-pyrimidinyl)methyl)-3-thiophencarboxylate;and (S)-N-valeryl-N-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-valine;and mixtures thereof.

The administration of the AT₁ antagonist can be accomplished by anyknown method of drug administration. Preferably, the AT₁ antagonist isadministered orally, parenterally, intravenously, intra-nasally, orepidurally. Dosage forms contemplated by the present invention includetablets, capsules, elixirs, suppositories, solutions, suspensions, andthe like. Also contemplated by the present invention are time-releaseand/or delay release dosage forms, including conventional pharmaceuticalcarrier, excipients, dispersants and the like.

The dosage range for the AT₁ antagonist is preferably from about 0.5 mgto about 800 mg over a period of about twenty-four hours, morepreferably, from about 0.5 mg to about 500 mg over a twenty-four hourperiod.

In alternate embodiments of the present invention, the AT₁ antagonistcan be administered in combination with a variety of other compounds andpharmaceutical actives. For example, the AT₁ antagonists can beadministered in combination with non-steroidal anti-inflammatory drugs(NSAID's), opiod drugs, antidepressant drugs, angiotensin convertingenzyme (ACE) inhibitors, diuretics, and the like, or mixtures thereof.

A non-limiting list of NSAID's contemplated for such a use includesibuprofen, diclofenac, piroxcam, naproxen sodium, naproxen, nambumetone,etodolac, ketorolac tromethamine, acetylsalicylic acid, sodiumsalicylate, diflunisal, sulindac, tolmetin sodium, mefanamic acid,meclofenamate sodium, fenoprofen and mixtures thereof. Preferable dosageranges of these NSAID's when used in combination with the AT₁antagonists are shown in Table II.

                  TABLE II                                                        ______________________________________                                                                       AMOUNT                                                                        of AT.sub.1 AN-                                              AMOUNT OF NSAID DRUG                                                                           TAGONIST                                       TYPE OF NSAID DRUG                                                                          mg/24 hours      mg/24 hours                                    ______________________________________                                        ibuprofen      200-3200        0.5-800                                        diclofenac    100-150          0.5-800                                        piroxcam      10-20            0.5-800                                        naproxen sodium                                                                              825-1375        0.5-800                                        naproxen       500-1500        0.5-800                                        nambumetone   1000-2000        0.5-800                                        etodolac       600-1200        0.5-800                                        ketorolac      40-150          0.5-800                                        tromethamine                                                                  acetylsalicylic                                                                              300-1800        0.5-800                                        acid/sodium                                                                   salicylate                                                                    diflunisal     250-1500        0.5-800                                        sulindac      150-400          0.5-800                                        tolmetin sodium                                                                              200-1800        0.5-800                                        mefanamic acid                                                                               675-1250        0.5-800                                        meclofenamate  50-400          0.5-800                                        sodium                                                                        fenoprofen     200-3200        0.5-800                                        ______________________________________                                    

A non-limiting list of opiod drugs contemplated for such a use includescodeine, morphine sulfate, hydroxymorphone, hydrocodone, oxycodone,meperidine and mixtures thereof. Preferable dosage ranges of these opioddrugs when used in combination with the AT₁ antagonists are shown inTable III.

                  TABLE III                                                       ______________________________________                                                      AMOUNT OF OPIOD                                                                             AMOUNT OF AT.sub.1                                              DRUG          ANTAGONIST                                        TYPE OF OPIOD DRUG                                                                          mg/24 hours   mg/24 hours                                       ______________________________________                                        codeine        30-3600      0.5-800                                           morphine sulfate                                                                             2-600        0.5-800                                           hydromorphone 1-20          0.5-800                                           hydrocodone   5-25          0.5-800                                           oxycodone     5-30          0.5-800                                           meperidine     50-1200      0.5-800                                           ______________________________________                                    

A non-limiting list of antidepressant drugs contemplated for such a useincludes amytriptyline HCl, amoxapine, desipramine HCl, doxepine HCl,imipramine HCl, maprotiline HCl, phenelzine sulfate, fluoxetine HCl,sertraline HCl, trazodone and mixtures thereof. Preferable dosage rangesof these antidepressant drugs when used in combination with the AT₁antagonists are shown in Table IV.

                  TABLE IV                                                        ______________________________________                                                                       AMOUNT                                                       AMOUNT OF        OF AT.sub.1 AN-                                TYPE OF ANTI- ANTIDEPRESSANT DRUG                                                                            TAGONIST                                       DEPRESSANT DRUG                                                                             mg/24 hours      mg/24 hours                                    ______________________________________                                        amytriptyline HCl                                                                           50-100           0.5-800                                        amoxapine     50-300           0.5-800                                        desipramine HCl                                                                             25-200           0.5-800                                        doxepine HCl  25-200           0.5-800                                        imipramine HCl                                                                              30-200           0.5-800                                        maprotiline HCl                                                                             20-100           0.5-800                                        phenelzine sulfate                                                                          15-60            0.5-800                                        fluoxetine HCl                                                                              10-80            0.5-800                                        sertraline HCl                                                                              50-200           0.5-800                                        trazodone     50-400           0.5-800                                        ______________________________________                                    

A non-limiting list of angiotensin converting enzyme inhibitorscontemplated for such a use includes quinipril, enalapril, captopril,benazepril, ramipril, trandolapril, lisinopril, fosinopril and mixturesthereof. Preferable dosage ranges of these ACE inhibitors when used incombination with the AT₁ antagonists are shown in Table V.

                  TABLE V                                                         ______________________________________                                                    AMOUNT OF ACE                                                                              AMOUNT OF AT.sub.1                                   TYPE OF ACE INHIBITOR    ANTAGONIST                                           INHIBITOR   mg/24 hours  mg/24 hours                                          ______________________________________                                        quinipril   10-80        0.5-800                                              enalapril    5-40        0.5-800                                              captopril    25-450      0.5-800                                              benazepril  10-40        0.5-800                                              ramipril    2.5-20       0.5-800                                              trandolapril                                                                              0.5-16       0.5-800                                              lisinopril   5-40        0.5-800                                              fosinopril  10-80        0.5-800                                              ______________________________________                                    

A non-limiting list of diuretics contemplated for such a use includesbenzthiazide, bumetanide, chlorthiazide, chlorthalidone, ethacrynicacid, furosemide, hydrochlorothiazide, hydroflumethiazide, metolazone,polythiazide, spironalactone, triameterene and mixtures thereof.Preferable dosage ranges of these diuretics when used in combinationwith the AT₁ antagonists are shown in Table VI.

                  TABLE VI                                                        ______________________________________                                                                    AMOUNT OF AT.sub.1                                            AMOUNT OF DIURETIC                                                                            ANTAGONIST                                        TYPE OF DIURETIC                                                                          mg/24 hours     mg/24 hours                                       ______________________________________                                        benzthiazide                                                                               25-100         0.5-800                                           bumetanide  15-10           0.5-800                                           chlorthiazide                                                                              0.5-1000       0.5-800                                           chlorthalidone                                                                            12.5-100        0.5-800                                           ethacrynic acid                                                                           12.5-200        0.5-800                                           furosemide  10-80           0.5-800                                           hydrochlorothiazide                                                                       12.5-100        0.5-800                                           hydroflumethiazide                                                                         25-100         0.5-800                                           metolazone  0.5-20          0.5-800                                           polythiazide                                                                              1-4             0.5-800                                           spironalactone                                                                             25-400         0.5-800                                           triameterene                                                                               50-300         0.5-800                                           ______________________________________                                    

While the invention has been described herein in terms of certainpreferred embodiments, those skilled in the art will recognize thatvarious modifications can be made without departing from the scope ofthe present invention.

I claim:
 1. A method of treating acute or chronic pain mediated by thesympathetic nervous system comprising administering to a patient aneffective amount of an AT₁ antagonist.
 2. A method according to claim 1,wherein said AT₁ antagonist is selected from the group consisting ofsodium2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo(4,5-b)pyridin-3-yl)methyl)quinolin-2-yl)benzoate;4'-((1,4'-dimethyl-2'-propyl(2,6'-bi-1H-benzimidazol)-1'-yl)methyl)-(1,1'-biphenyl)-2-carboxylicacid;5-methyl-7-propyl-8-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1,2,4-triazolo(1,5-c)pyrimidin-2(3H)-one;1-(N-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl)-N-valerolylaminomethyl)cyclopentane-1-carboxylicacid;1-((2'((i-pentyloxycarbonylamino)sulfonyl)-3-fluoro-(1,1'-biphenyl)-4-yl)methyl)-5-(2-(N-butyryl-N-pyridin-3-ylamino)propionyl)-4-ethyl-2-propyl-1H-imidazole,potassium salt;4-ethyl-2-n-propyl-1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic acid; 1H-Imidazole-5-carboxylic acid,4-(pentafluoroethyl)-2-propyl-1-((2'-1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl-(CAS);1H-imidazole-5-methanol,2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-,monopotassium salt (CAS);3-((2'carboxybiphenyl-4-yl)methyl)-2-cyclopropyl-7-methyl-3H-imidazo(4,5-b)pyridine;1H-imidazole-5-carboxylic acid,1-((3-bromo-2-(1H-tetrazol-5-yl)phenyl)-5-benzofuranyl)methyl)-2-butyl-4-chloro-(CAS);2-butyl-4-chloro-1((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxylicacid,-1-(ethoxycarbonyloxy)ethylester, K+ salt;3-methoxy-2,6-dimethyl-4-((2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methoxy)pyridine;6-(benzoylamino)-7-methyl-2-propyl-3-((2'-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)(1,1')-biphenyl-4-yl)methyl)-3H-imidazo(4,5-b)pyridine;6-(N-acetyl-N-methylamino)-2-propyl-3-(2'-tetrazol-5-yl)-biphen-4-yl)methyl)quinazolin-4-(3H)-one;1,1-dimethylethyl-2-(4'-(1-(3-(5-butyl)-2-oxo-(2-trifylphenyl)-(1,3,4)-trazolyl)methyl)biphenyl)sulfonylaminocarboxylate;5-((3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl)-2-(2-(1H-tetrazol-5-ylphenyl))pyridine;2-n-butyl-4-spirocyclopentane-1-(((2'-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-imidazolin-5-one;3-(2-butyl-1-(4-carboxybenzyl)-1H-imidazol-5-yl)-2-(2-thienylmethyl)-2-(E)-propenoicacid;6-butyl-2-(2-phenylethyl)-5-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-4(1H)-Pyrimidinone;2,7-diethyl-5-((2'-(5-tetrazolyl)biphenyl-4-yl)methyl)-5H-pyrazolo(1,5-b)(1,2,4)triazole;1H-imidazole-5-carboxylic acid,1-((3-bromo-2-(2-(1H-tetrazol-5yl)phenyl)-5-benzofuranyl)methyl)-2-butyl-4-chloro-(CAS);1H-benzimidazole-7-carboxylic acid,2-ethoxy-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-,1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester,-(CAS); methyl2-((4-butyl-2-methyl-6-oxo-5-((2'-(1H-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl)methyl)-1(6H)-pyrimidinyl)methyl)-3-thiophencarboxylate;and (S)-N-valeryl-N-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-valine,and mixtures thereof.
 3. A method according to claim 1, wherein saidadministering comprises administering at least one AT₁ antagonistorally.
 4. A method according to claim 1, wherein said administeringcomprises administering at least one AT₁ antagonist intravenously.
 5. Amethod according to claim 1, wherein said administering comprisesadministering at least one AT₁ antagonist intra-nasally.
 6. A methodaccording to claim 1, wherein said administering comprises administeringat least one AT₁ antagonist epidurally.
 7. A method according to claim1, wherein said administering comprises administering at least one AT₁antagonist in an amount from about 0.5 to about 800 mg over a period ofabout twenty-four hours.
 8. A method according to claim 1, wherein saidAT₁ antagonist is administered in combination with a drug selected fromthe group consisting of a non-steroidal anti-inflammatory drug, anopioid drug, an antidepressant drug, an angiotensin converting enzymeinhibitor, a diuretic, and mixtures thereof.
 9. A method according toclaim 8, wherein said non-steroidal anti-inflammatory drug is selectedfrom the group consisting of ibuprofen, diclofenac, piroxcam, naproxensodium, naproxen, nambumetone, etodolac, ketorolac tromethamine,acetylsalicylic acid, sodium salicylate, diflunisal, sulindac, tolmetinsodium, mefanamic acid, meclofenamate sodium, fenoprofen and mixturesthereof.
 10. A method according to claim 8, wherein said opioid drug isselected from the group consisting of codeine, morphine sulfate,hydroxymorphone, hydrocodone, oxycodone, meperidine and mixturesthereof.
 11. A method according to claim 8, wherein said antidepressantdrug is selected from the group consisting of amytriptyline HCl,amoxapine, desipramine HCl, doxepine HCl, imipramine HCl, maprotilineHCl, phenelzine sulfate, fluoxetine HCl, sertraline HCl, trazodone andmixtures thereof.
 12. A method according to claim 8, wherein saidangiotensin converting enzyme inhibitor is selected from the groupconsisting of quinipril, enalapril, captopril, benazepril, ramipril,trandolapril, lisinopril, fosinopril and mixtures thereof.
 13. A methodaccording to claim 8, wherein said diuretic is selected from the groupconsisting of benzthiazide, bumetanide, chlorthiazide, chlorthalidone,ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide,metolazone, polythiazide, spironalactone, triameterene and mixturesthereof.
 14. A method of treating sympathetically mediated paindisorders comprising administering to a patient an effective amount ofan AT₁ antagonist.